There is a growing realization that human subjects with anxiety disorders exhibit abnormalities in how they acquire and/or extinguish conditioned fear responses. Thus, understanding how anxiety and conditioned fear interact at the neuronal level has direct clinical relevance. The neuropeptide corticotropin-releasing factor (CRF) is released throughout the brain under conditions of stress and anxiety. The amygdala contains particularly dense concentrations of CRF receptors whose activation leads to anxious behaviors. Yet the modulation of fear learning by this neuropeptide and indeed the interaction between anxiety and fear learning has not been comprehensively explored. We propose to examine this question by using multiple complementary methods. We will first analyze the anatomical distribution of CRF receptors within the basolateral nucleus of the amygdala (BLA), determining whether these receptors are located on the principal excitatory neurons of the BLA and/or on subsets of inhibitory interneurons. We will next examine behaviorally how CRF modulates fear learning and expression. Finally, using in vitro electrophysiology, we will study how CRF affects electrophysiological properties of BLA neurons and synaptic plasticity. Together, the experiments in this proposal represent an important step in understanding how CRF modulates Pavlovian fear conditioning. Thus, the results of this project may yield fundamental insights into the causes of anxiety disorders and provide a foundation for clinical investigation and pharmaceutical development. PUBLIC HEALTH RELEVANCE: Many anxiety disorders can be characterized by abnormalities in acquiring or extinguishing conditioned fear. This project will explore the relationship between a key neuropeptide associated with anxiety and the ability to learn and express conditioned fear responses.